Bioactive chromogranin-A derived peptides that act via different mechanisms for the prevention and treatment of cardiovas

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BACKGROUND: The renin-angiotensin-system and especially the angiotensin peptides play a cen-tral role in blood pressure regulation. Here, we hypothesize that a yet unknown peptide is in-volved in the action of Ang-II modulating the vasoregulatory effects as a cofactor.
METHODS AND RESULTS: The peptide with vasodilatory properties was isolated from adrenal glands chromatographically. The effects of thispeptide were evaluated in-vitro and in-vivo, and the receptor affinity was analysed. The plasma concentration in humans was quantified in chronic kidney disease patients, heart failure patients and healthy controls. The amino acid se-quence of the peptide from bovine adrenal glands was HSSYEDELSEVL EKPNDQAE PKEVTEEVSSKDAAE, which is a degradation product of Chromogranin-A. The sequence of the peptide isolated from human plasma was HSGFEDELSEVLENQSSQAELKEAVEEPSSKDVME. Both peptides diminished significantly the vasoconstrictive effect of Ang-II in-vitro. Therefore, we named the peptide "vasoconstriction inhibiting factor" (VIF). The vasoregulatory effects of VIF are mediated by the AT2-receptor. VIF impairs Ang-II-induced phosphorylation of the p38MAPK-pathway but not of ERK1/2. The vasodilatory effects were confirmed in-vivo. The plasma concentration was significantly in-creased in renal and hear failure patients.
CONCLUSIONS: VIF is a vasoregulatory peptide which modulates the vasoconstrictive effects of Ang-II by acting on the AT2-receptor. It is likely that the increase in VIF may serve as a counter-regulatory effect to defend against hypertension. The identification of this target may help us to understand the pathophysiology of renal and heart failure and may form a basis for the develop-ment of new strategies for the prevention and treatment of cardiovascular disease.

Salem S, Jankowski V, Asare Y, et al. Identification of the Vasoconstriction-Inhibiting Factor (VIF), a Potent Endogenous Cofactor of Angiotensin II Acting on the Angiotensin II Type 2 Receptor. Circulation. 2015;131(16):1426-34.

Catestatin (CST), the Chromogranin A (CgA)-derived cationic and hydrophobic peptide, firstly recognized as an endogenous inhibitor of catecholamine secretion, functions as a physiological brake of the adreno-sympathetic-chromaffin system. Its wide spectrum of activities includes relevant multilevel cardiovascular and antihypertensive influences. At central systemic level, CST seems to modulate the autonomic cardiovascular control possibly acting on baroreceptor afferent fibers of the nucleus tractus solitarius. This, as well as clinical and experimental (CgA-KO mice) evidences point to an important role of CST in the determinism and prevention of essential hypertension. At organ level, CST exerts myocardial (negative inotropy and lusitropy) effects and potently vasodilates endothelin-1 (ET-1)-preconstricted coronaries through ?2-adrenergic receptor (AR)-Gi/o protein-nitric oxide (NO)-cGMP signalling, while counterbalancing ? adrenergic (ISO) stimulation. The contractile myocardial effects have been deeply analysed in fish and amphibian hearts, highlighting finely diversified mechanisms of action. CST also acts as cardioprotective agent in both pre- and post-conditioning through NO-dependent mechanisms implicating the Reperfusion Injury Salvage Kinase (RISK) signalling and the activation of mitoKATP channels. The CST-elicited cardiotropic and coronarotropic influences, along with the recently discovered proangiogenic and regulatory effects in glucose and lipid metabolism, contribute to delineate an integrated and updated picture of the peptide which emerges as a pleiotropic hormone with a wide range of cytokine-like characteristics. The aim of this review is to interlock some older and more recent evidences which may help to better perceive the subtle links and differences among the puzzle pieces that still need to be deciphered.

Mazza R, Tota B, Gattuso A. Cardio-vascular activity of catestatin: interlocking the puzzle pieces. Curr Med Chem. 2015;22(3):292-304.

Catestatin (Cst) is a 21-amino acid peptide deriving from Chromogranin A. Cst exerts an overall protective effect against an excessive sympathetic stimulation of cardiovascular system, being able to antagonize catecholamine secretion and to reduce their positive inotropic effect, by stimulating the release of nitric oxide (NO) from endothelial cells. Moreover, Cst reduces ischemia/reperfusion (I/R) injury, improving post-ischemic cardiac function and cardiomyocyte survival. To define the cardioprotective signaling pathways activated by Cst (5 nM) we used isolated adult rat cardiomyocytes undergoing simulated I/R. We evaluated cell viability rate with propidium iodide labeling and mitochondrial membrane potential (MMP) with the fluorescent probe JC-1. The involvement of Akt, GSK3?, eNOS and phospholamban (PLN) cascade was studied by immunofluorescence. The role of PI3K-Akt/NO/cGMP pathway was also investigated by using the pharmacological blockers wortmannin (Wm), L-NMMA and ODQ. Our experiments revealed that Cst increased cell viability rate by 65% and reduced cell contracture in I/R cardiomyocytes. Wm, L-NMMA and ODQ limited the protective effect of Cst. The protective outcome of Cst was related to its ability to maintain MMP and to increase AktSer473, GSK3?Ser9, PLNThr17 and eNOSSer1179 phosphorylation, while treatment with Wm abolished these effects. Thus, the present results show that Cst is able to exert a direct action on cardiomyocytes and give new insights into the molecular mechanisms involved in its protective effect, highlighting the PI3K/NO/cGMP pathway as the trigger and the MMP preservation as the end point of its action.

Bassino E, Fornero S, Gallo MP, et al. Catestatin exerts direct protective effects on rat cardiomyocytes undergoing ischemia/reperfusion by stimulating PI3K-Akt-GSK3β pathway and preserving mitochondrial membrane potential. PLoS ONE. 2015;10(3):e0119790.

PURPOSE: To verify the effect of vasostatin-1 (VS-1), an anti-angiogenic fragment of chromogranin A, in the prevention of choroidal neovascularization (CNV) in an established mouse model of laser-induced ocular neovascularization.
METHODS: Bruch's membrane, the innermost layer of the choroid, was broken by laser photocoagulation in C57/Bl6 mice, to induce CNV. Mice were then treated daily for 14 days by intraperitoneal injection of VS-1 or vehicle (6 mice/group). CNV and vascular leakage were measured at three time-points (day 0, 7 and 14) in vivo by spectral domain optical coherence tomography (OCT) and fluorescein angiography (FA). Ex vivo analysis of CNV was also performed at day 14 by confocal microscopy analysis of dextran-perfused choroidal flat-mounts.
RESULTS: In vivo analyses showed that VS-1 significantly reduced CNV at day 14 (p = 0.03) and vascular leakage at day 7 (p = 0.01) and 14 (p = 0.04). Ex vivo confocal microscopy analysis of CNV performed on dextran-perfused choroidal flat-mounts at day 14 confirmed the protective activity of VS-1 (p = 0.01). A significant correlation between the results of in vivo and ex vivo analyses of CNV was also observed (p = 0.001, R2 = 0.81).
CONCLUSION: The results indicate that VS-1 can prevent CNV and vascular leakage in a mouse model of ocular neovascularization, suggesting that this polypeptide might have therapeutic activity in human ocular diseases that are complicated by neovascularization or excessive vascular permeability.

Maestroni S, Maestroni A, Ceglia S, et al. Effect of chromogranin A-derived vasostatin-1 on laser-induced choroidal neovascularization in the mouse. Acta Ophthalmol. 2015;93(3):e218-22.

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